Geldanamycin (GM; NSC 122750) is a benzoquinoid ansamycin produced by a variant of Streptomyces hygroscopicus. The compound exhibits potent (IC50 < 10 nM) cytotoxicity against highly malignant neuroectodermal cell lines, originating from both the peripheral and central nervous system, while more differentiated neuroblastoma and normal hematopoietic cell lines were relatively resistant. In addition, potent cytotoxicity against human prostate cancer cells in vitro has also been demonstrated. In consideration of these promising observations, studies to characterize the pharmacokinetics and acute toxicity of GM in the mouse and dog were undertaken. These studies demonstrated that the drug was subject to rapid elimination by both species. Following administration of the maximum tolerated doses, given as a single bolus i.v. injection, plasma concentrations of GM remained above 0.1 fg/ml for only 4 hr in mice (dose = 20.6 mg/kg) and for approximately 90 min in a dog (dose = 1.8 mg/kg). The principal toxic effects of the drug in the dog appeared to be directed against the liver, there was some evidence consistent with gastrointestinal toxicity and nephrotoxicity. Therefore, although single bolus i.v. doses of GM with minor reversible toxicity provided plasma levels exceeding the concentration required to elicit in vitro growth inhibition of sensitive cell lines, its short systemic duration and absence of significant oral bioavailability indicate that a continuous infusion schedule may be required for optimal therapeutic effects. However, the compound is highly insoluble in water and a clinically acceptable parenteral formulation has not been developed. Therefore, efforts to identify a derivative with suitable solubility characteristics for an injectable dosage form with retained antineoplastic activity have been initiated.